Genetic Pathways Determine Susceptibility to Dengue Shock Syndrome

MedicalResearch.com Interview with:

CDC/ Frederick Murphy

This transmission electron microscopic (TEM) image depicts a number of round, Dengue virus particles that were revealed in this tissue specimen. CDC image

Luisa Pereira PhD
Institute for Research and Innovation in Health
University of Porto 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: By using admixture mapping along the genome in Thai cohorts, we were able to identify new candidate genes conferring protection/susceptibility to dengue fever. A very interesting result was that the set of genes differed with the dengue phenotype: genes coding proteins that may link to the virus, conditioning its entrance in the host cells and mobility therein were associated with the less severe phenotype; genes related with blood vessels permeability were associated with the dengue shock syndrome.  Continue reading

Tetravalent Vaccine Proves Promising In Protecting Children From Dengue

MedicalResearch.com Interview with:
Vianney Tricou DPhil
Takeda Vaccines Pte Ltd
Singapore

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Dengue fever is a painful, debilitating mosquito-borne disease caused by any one of the four closely related dengue virus serotypes. Forty percent of the world’s population lives under the threat of dengue, with approximately 390 million infections and 20,000 deaths occurring globally each year. Dengue virus can infect people of all ages and is a leading cause of serious illness among children in some countries in Latin America and Asia. Takeda is developing a dengue vaccine candidate to safely protect children and adults living in, or traveling to, endemic areas against all four dengue virus serotypes, regardless of previous dengue virus exposure. 

Takeda’s tetravalent dengue vaccine candidate (TAK-003) is based on a live, attenuated dengue serotype 2 virus, which provides the genetic ‘backbone’ for all four vaccine viruses. Takeda’s ongoing Phase 2 DEN-204 study was designed to assess the safety and immunogenicity of different dose schedules of TAK-003 in approximately 1,800 healthy children and adolescents ages two through 17 years living in dengue-endemic countries in Latin America and Asia. Participants of the DEN-204 trial received either one primary dose of TAK-003, two primary doses of TAK-003 administered three months apart, one primary dose of TAK-003 followed by a booster dose one year later, or a placebo. Eighteen-month interim data showed that that TAK-003 is associated with a reduction in the incidence of dengue in the study participants. Data also showed that TAK-003 induced sustained antibody responses against all four serotypes of dengue virus, regardless of previous dengue exposure and dosing schedule.

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Phase 2 Trial of Takeda’s Dengue Vaccine Demonstrates Immune Response Against All 4 Strains

MedicalResearch.com Interview with:

Dr Vianney Tricou DPhil Takeda Vaccines Singapore

Dr. Vianney Tricou

Dr Vianney Tricou DPhil
Takeda Vaccines
Singapore

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Dengue fever is a painful, debilitating mosquito-borne disease caused by any one of four closely related dengue virus serotypes, and persons living in dengue endemic regions may be affected by dengue more than once in their lifetime. Some individuals with dengue fever are hospitalized and may need intensive therapy to prevent shock and death, and severe dengue is a leading cause of hospitalization and death among children and adults in some Asian and Latin American countries. About half of the world’s population lives under the threat of dengue and the disease has a significant medical and economic impact in the tropical and subtropical regions of the world where dengue is endemic.

Takeda is committed to improving global public health and to developing a life-saving dengue vaccine candidate for people around the world. Takeda’s tetravalent dengue vaccine candidate (TAK-003) is based on a live-attenuated dengue serotype 2 virus (DENV-2), which provides the genetic ‘backbone’ for all four attenuated dengue virus serotypes present in the vaccine. Takeda’s Phase 1 and Phase 2 clinical study program includes 8 studies to date that assess the safety and/or immunogenicity of this candidate, before moving into Phase 3.

Takeda’s ongoing Phase 2 DEN-204 study is designed to assess the safety and immunogenicity of one- and two-dose schedules of TAK-003 in 1,794 healthy children and adolescents ages two through 17 years living in dengue-endemic countries in Latin America and Asia.

As published in The Lancet Infectious Diseases in March 2017, an interim analysis of DEN-204 data indicated that TAK-003 elicited antibody responses to all four dengue serotypes in the population studied, regardless of whether they had previous dengue exposure.

A second TDV dose improved antibody responses against DENV-3 and DENV-4 in children who were seronegative before vaccination. In this study, the safety profile was consistent with that observed in earlier Phase 1 and 2 studies.
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Inflammation Caused By Mosquito Bites Helps Viral Infections Spread

MedicalResearch.com Interview with:
Clive McKimmie PhD
Research Fellow,
Virus Host Interaction Team (VHIT),
University of Leeds
St James’ University Hospital
Leeds UK

MedicalResearch.com: What is the background for this study?

Response: With the rapid spread of Zika in the Americas, attention has been drawn to this group of neglected mosquito-borne viral infections. The Zika virus is not alone in causing problems, others such as dengue and chikungunya viruses are infecting millions of people each year. Yet there’s little doctors can do to help people who get sick.
When mosquitoes bite you they can transmit these disease causing viruses. We don’t understand what happens during the early stages of infection very well. However, it is known that the mosquito bite itself somehow helps the virus to infect your body.

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Dengue During Pregnancy Linked to Adverse Fetal Outcomes

MedicalResearch.com Interview with:
Mrs Enny S Paixão

London School of Hygiene & Tropical Medicine
London UK 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Dengue is a vector borne disease endemic in more than 100 countries (mainly in South America and southeast Asia) and is spreading to new areas, with outbreaks of increasing magnitude and severity. It is estimated that each year, 390 million people are infected with dengue and 96 million develop clinical symptoms. Despite of the importance of this disease, the effects of disease during pregnancy on fetal outcomes remain unclear. Using the published scientific literature, we investigated the risk of stillbirth, miscarriage, preterm birth, and low birth weight for women who had dengue infection during pregnancy.

This study showed some evidence that dengue infection alone, in the absence of clinical symptoms, does not affect the outcome of pregnancy, but also that clinical dengue during pregnancy seems to increase the frequency of stillbirth, prematurity, and low birthweight.

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Scientists Consider Using Bacteria To Deliver Lethal RNA to Zika Spreading Mosquitoes

MedicalResearch.com Interview with:

Prof Paul Dyson Institute of Life Science Swansea University Medical School Singleton Park Swansea UK

Prof. Paul Dyson

Prof Paul Dyson
Institute of Life Science
Swansea University Medical School
Singleton Park
Swansea UK

Medical Research: What is the background for this study? What are the main findings?

Prof. Dyson: The spread of insect-vectored viruses such as Dengue and, more recently, Zika, underline the urgent necessity to develop new technologies to control insect disease vectors that, due to human activity, are spreading globally. The concept of using RNAi in insects is not new and is widely used as a research tool in the model organism Drosophila melanogaster. However, adapting RNAi for use in non-model insects has been slow, almost entirely due to the problem of delivering interfering RNA to the insect. Manual injection is a less than optimal means of delivery for larger insects, while including interfering RNA in a food source can be effective in smaller insects in the laboratory. But neither delivery system is suited for field applications of RNAi as a biocide. Faced with this challenge, we (myself and Dr Miranda Whitten) conceived the concept of symbiont-mediated RNAi and have advanced it with support from the UK BBSRC and the Gates Foundation, establishing it as a viable mechanism of delivery of RNAi in

(a) a tropical disease vector, Rhodnius prolixus, a vector of Chagas disease, exemplified by targeting insect fertility, and

(b) a globally invasive vector of plant disease, Western Flower Thrips, targeting larval growth. Interfering RNA is actively produced by symbiotic insect bacteria that multiply within the host.

Critical to the technology is to ensure the stability of RNA synthesis by these bacteria. The interfering RNA is then released by the bacteria, absorbed and systemically circulated within the host, thereby causing knock-down of gene expression in specific tissues. We have exploited this technology to severely impair fertility of Rhodnius prolixus, and to cause mortality of developing larvae of Western Flower Thrips. As a biocide, the technology offers exquisite specificity due to the co-evolution and co-dependencies of the symbiont and its insect host, combined with the sequence-specificity of the RNAi. Moreover, development of resistance is highly improbable.

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Not All Dengue Viruses Have Have Same Potential For Disease Outbreaks

MedicalResearch.com Interview with:
Dr. Eng Eong Ooi BMBS PhD FRCPath

Associate Professor & Deputy Director
Program in Emerging Infectious Diseases
Duke-NUS Graduate Medical School
Singapore

Medical Research: What is the background for this study? What are the main findings?

Response: Dengue prevention continues to rely exclusively on vector control guided by disease and virologic surveillance. The latter has focused on detecting changes in the prevalence of the four antigenically distinct viral serotypes as, in general terms, herd immunity depends on long-lived serotype-specific antibodies.  However, epidemiological observations have indicated that a small number of changes within the viral genome have also been associated with several major outbreaks, without any change in viral serotype.  Identifying the genetic changes that alter viral fitness epidemiologically would thus be important to differentiate strains that have a greater potential of causing epidemics and targeted for control.

Using the 1994 outbreak in Puerto Rico as a case in point, we identified nucleotide substitutions in the 3’ untranslated region (3’UTR) of the viral genome as critical determinants of dengue virus’ epidemiological fitness.  Mechanistically, mutations in the 3’UTR altered secondary viral RNA structures and changed the relative proportion of genomic to subgenomic RNA of the virus in infected cells.  The epidemiologically fitter viruses produced larger amounts of subgenomic to genomic RNA.  This subgenomic RNA then binds a host protein, TRIM25, which is a E3 ubiquitin ligase that polyubiquitylates RIG-I to amplify and sustain signalling for type-I interferon expression.  By binding to TRIM25, the subgenomic RNA of dengue virus inhibits the activation and thus enzymatic function of TRIM25.  We suggest that with reduced interferon expression, the virus was thus able to spread more effectively from cell to cell within the infected individuals to reach viremia levels for further subsequent mosquito-borne transmission. Continue reading

Disposable Device Can Detect Dengue Antibodies in Saliva in 20 Minutes

MedicalResearch.com Interview with:
Professor Jackie Ying
Institute of Bioengineering and Nanotechnology
The Nanos, Singapore

Medical Research: What is the background for this study? What are the main findings?

Response: The Institute of Bioengineering and Nanotechnology (IBN) has developed a paper-based disposable device that will allow dengue-specific antibodies to be detected easily from saliva within 20 minutes.

Currently, dengue infection is diagnosed in the laboratory by testing the patient’s blood sample for the presence of dengue antigens or antibodies. IBN’s device, on the other hand, is capable of detecting IgG, a dengue-specific antibody found at the onset of secondary infections, directly from saliva in one step.

Credit: IBN, A*STAR

This is a 3-D model of IBN’s rapid test kit that detects dengue-specific antibodies.

Unlike blood samples, saliva can be collected easily and painlessly for rapid point-of-care diagnostics. However, unlike other body fluids, it cannot be applied directly to commercially available test kits as it would cause the sensor nanoparticles to stick haphazardly to the test strip. In addition, conventional paper-based tests are not designed to handle the larger sample volume of saliva required.

As described in the journal Lab on a Chip, the IBN researchers used an innovative stacking flow design to overcome key challenges faced by existing lateral flow devices, which are not designed to handle large volume of saliva samples.

In IBN’s device, different flow paths are created for samples and reagents through a multiple stacked system. This allows the saliva sample to flow separately through a fiber glass matrix, which removes the substances that would interfere with the nanoparticle-based sensing system before it mixes with the sensor nanoparticles. IBN’s device configuration also helps to regulate the flow in the test strip, generating uniform test lines for more accurate results.

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Road Networks Predict Dengue and Chikungunya Mosquito Spread

'Tiger Mosquito' Aedes albopictus female mosquito

‘Tiger Mosquito’
Aedes albopictus female mosquito

MedicalResearch.com Interview with:
Jose R. Loaiza
Smithsonian Tropical Research Institute,
Panama City, Panama, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología,  Universidad de Panamá, Ciudad de Panamá, Panamá

 


Medical Research: What is the background for this study?

Response: The mosquito Aedes albopictus is a worldwide vector of both Dengue and
Chikungunya viruses.

This species invaded Panama in 2002, and it expanded
across much of the country since that time. Our main goal was to
determine the factors (e.g., ecological and non-ecological) associated
with its expansion, and to comment on the implications for vector and
disease control programs elsewhere in the American tropics.

Medical Research: What are the main findings?

Response: We found that road networks alone best predicted the distribution of Ae.
albopictus in Panama over other variables such as population density and
climate. Our data explain the invasion mode of this mosquito species on a
local level and demonstrate a remarkable population expansion velocity
across the country. Ae. albopictus is likely moving across the landscape
as immature stages (i.e., larvae and pupae) in open water, such as used
tires.

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New Dengue Vaccine Trial in Latin America Demonstrates Efficacy

Gustavo Dayan, MD Director, Clinical Development Sanofi Pasteur  Discovery Drive Swiftwater, PA 18370MedicalResearch.com Interview with:
Gustavo Dayan, MD

Director, Clinical Development
Sanofi Pasteur  Discovery Drive
Swiftwater, PA 18370

Medical Research: What is the background for this study? What are the main findings?

Dr. Dayan: This is the first dengue vaccine efficacy trial conducted in Latin America. The trial met its primary objective showing an efficacy of 60.8% against symptomatic VCD (virologically confirmed dengue) after a 3-dose vaccination schedule. Serotype-specific efficacy was also demonstrated against all four serotypes. Furthermore, the dengue vaccine candidate effectively reduced hospitalization due to dengue by 80.3% and severe dengue disease by 95.5% over the 25-month study period. Continue reading